This application claims the benefit of European Patent Application No. 01 400 214.1 filed Jan. 26, 2001.
This invention relates to a method for preventing and treating visceral pain, and gastrointestinal disorders such as functional bowel disorders and inflammatory bowel diseases, through the use of effective amounts of bicyclic amino acids.
The viscera encompasses the organs of the abdominal cavity. These organs include the sex organs, spleen and part of the digestive system. Pain associated with the viscera can be divided into digestive visceral pain and non digestive visceral pain.
Commonly encountered gastrointestinal (GI) disorders include the functional bowel disorders (FBD) and the inflammatory bowel diseases (IBD). These GI disorders include a wide range of disease states that are currently only moderately controlled, includingxe2x80x94for FBD, gastro-esophageal reflux, dyspepsia, the irritable bowel syndrome (IBS) and functional abdominal pain syndrome (FAPS), andxe2x80x94for IBD, Crohn""s disease, ileitis, and ulcerative colitis, and all regularly produce visceral pain. It has been shown recently in these pathologies, in particular the irritable bowel syndrome and dyspepsia, that the visceral pain threshold is decreased, indicating a visceral hypersensitivity. Other types of visceral pain include the pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
Few drugs are known to act selectively upon GI disorder-associated hypersensitivity (Farthing M. J. (1998) Drugs 56:11-21).
Available treatments of pain fall into two main categories: 1) nonsteroidal anti-inflammatory drugs, used to treat mild pain, but whose therapeutic use is limited by GI adverse effects (gastric erosion, peptic ulcer formation, inflammation of the duodenum and colon); 2) morphine and related opioids, used to treat moderate to severe pain but whose therapeutic use is limited by undesirable side effects including constipation, respiratory depression, tolerance, and abuse potential.
International patent publication WO 99/21824 disclose the use of cyclic amino acids and derivatives thereof for use in treating gastrointestinal disorders such as irritable bowel syndrome.
There is a need for drugs that can alleviate visceral pain without undesirable side effects.
It has now been found that compounds of formula I-IV (outlined below) are useful for the treatment of disorders such as visceral pain, FBD such as gastro-esophageal reflux, dyspepsia, IBS and FAPS, and IBD such as Crohn""s disease, ileitis, and ulcerative colitis, and other types of visceral pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis. The inventors have unexpectedly found that the compounds of formula I-IV have the capacity to prevent or treat disorders associated with visceral pain such as:
FBD, including gastro-esophageal reflux, dyspepsia, IBS and FAPS, and
IBD including Crohn""s disease, ileitis, and ulcerative colitis, and
other types of visceral pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis.
This invention provides a method for preventing and treating visceral pain and GI disorders, including FBS and IBD, comprising administering to a subject in need of treatment an effective amount of a compound of formula I-IV: 
or a pharmaceutically acceptable salt thereof, wherein n is an integer of from 1 to 4. Where there are stereocenters, each center may be independently R or S.
Preferred compounds of the invention are those of formulae I-IV above wherein n is an integer of from 2 to 4.
Other preferred compounds are those of Formula I above.
Especially preferred compounds are:
(1xcex1,6xcex1,8xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid, and
(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid.
A most preferred compound is (1xcex1,3xcex1,5xcex1)-3-aminomethyl-bicyclo[3.2.0]heptane-3-acetic acid, of formula Ia: 
Other preferred compounds are those selected from
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,5xcex2)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,5xcex2)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,5xcex2)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,3xcex1,5xcex1)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,3xcex1,5xcex1)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex1,8xcex1)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex1,9xcex1)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
(1xcex1,3xcex1,5xcex1)(3-Aminomethyl-bicyclo[3.1.0]hex-3-yl)-acetic acid,
(1xcex1,3 xcex2,5xcex1)(3-Aminomethyl-bicyclo[3.2.0]hept-3-yl)-acetic acid,
(1xcex1,3xcex2,5xcex1)(2-Aminomethyl-octahydro-pentalen-2-yl)-acetic acid,
(1xcex1,6xcex1,8xcex2)(2-Aminomethyl-octahydro-inden-2-yl)-acetic acid,
(1xcex1,7xcex1,9xcex2)(2-Aminomethyl-decahydro-azulen-2-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyelo[4.2.0]oct-3-yl)-acetic acid,
((3xcex1R,5R,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1R,5S,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5S,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5R,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid, ((2R,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1S,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1S,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1R,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2R,4xcex1R,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((1R,3R,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3S,6S)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3S,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1S,3R,6R)-3-Aminomethyl-bicyclo[4.1.0]hept-3-yl)-acetic acid,
((1R,3R,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1R,3S,6R)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3S,68)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((1S,3R,6S)-3-Aminomethyl-bicyclo[4.2.0]oct-3-yl)-acetic acid,
((3xcex1,5R,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1R,5S,7xcex1R)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5S,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((3xcex1S,5R,7xcex1S)-5-Aminomethyl-octahydro-inden-5-yl)-acetic acid,
((2R,4xcex1R,8xcex1R)-2-Aminomethyl-dctahydro-naphthalen-2-yl)-acetic acid,
((2S,4xcex1S,8xcex1R)-2-Aminomethyl-decahydro-naphthalen-5-2-yl)-acetic acid,
((2S,4xcex1R,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-5-2-yl)-acetic acid,
((2R,4xcex1S,8xcex1S)-2-Aminomethyl-decahydro-naphthalen-2-yl)-acetic acid,
((2R,4xcex1R,9xcex1R)-2-Aminomethyl-decahydro-bentzocyclophepten-2-yl)-acetic acid,
((2R,4xcex1R,9xcex1R)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid,
((2S,4xcex1S,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid, and
((2R,4xcex1S,9xcex1S)-2-Aminomethyl-decahydro-benzocyclophepten-2-yl)-acetic acid.
This invention also concerns the use of a compound of formula I-IV for the preparation of a medicament useful for preventing or treating visceral pain and gastrointestinal disorders such as:
FBD including gastro-esophageal reflux, dyspepsia, IBS, FAPS, and
IBD including Crohn""s disease, ileitis, and ulcerative colitis,
other types of visceral pain associated with dysmenorrhea, pelvic pain, cystitis and pancreatitis, in particular by the oral route.